DESCRIPTION: Temporomandibular disorders (TMDs) are characterized by chronic muscle tenderness and pain in the masticatory muscles and/or temporomandibular joints. The disease disproportionately affects women. A variety of etiologic factors have been suggested as the cause of this pain and dysfunction in the temporomandibular system. Head or neck trauma is highly correlated with the development of clinical symptoms of TMDs. Masticatory muscles have different biochemical properties as compared to other skeletal muscles which may increase the vulnerability to trauma, affect the reparative process as well as the response to inflammatory mediators normally released during tissue damage. One of the features of TMDs is the spread of pain from a localized trauma to involve numerous masticatory structures. Activation of nociceptive neurons during tissue damage leads to release of inflammatory neuropeptides.. Such activation and release may result in the release of similar peptides from surrounding intramuscular neurons, leading to an amplification of localized immune or inflammatory responses which occur during tissue damage. The overall goals of this proposal are to 1) define the response of the masseter muscle to localized trauma and 2) evaluate the action of inflammatory peptides both on reparative processes within the muscle and on stimulation of masticatory afferents. An overall theme to these studies is that sex hormones differentially affect the response of the masseter muscle to injury or inflammation. Therefore, in all cases they will examine the gender based differences in specific tissue responses. The specific hypotheses to be tested are: 1) the normal regenerative response to localized injury in the masseter muscles differs from that in limb muscle; 2) focal injury to the masseter muscles stimulates productions of inflammatory peptides in masticatory afferent neurons; 3) perturbations of the temporal expression of inflammatory peptides alter the normal response of masseter muscle to localized injury. Gene transfer into skeletal muscle provides an approach to define the role of specific gene products in tissue pathology. Using gene transfer in mice, the action of inflammatory mediators on the masseter and on masticatory afferents can be directly tested. Elucidation of the role of inflammatory mediators in masticatory muscles is important for both understanding the etiology of and designing the novel therapeutic strategies for the treatment of TMDs.